With an estimated annual incidence of 300,000-350,000 and accounting for 50% of all cardiovascular deaths in the US, sudden cardiac death (SCD) is a condition with significant implications for public health. Survival among out-of-hospital cardiac arrest victims remains <5%, making SCD prediction and prevention essential. However, current SCD risk stratification methodology, largely based on identification of severe left ventricular (LV) systolic dysfunction (LV ejection fraction, LVEF <35%), is inadequate. While some novel risk markers have been identified, no effective risk stratification tool has been adopted, and prediction of SCD in individuals with preserved LVEF (LVEF ?50%) has not been addressed. The overall hypothesis of this proposal is that predictors of SCD in patients with preserved LVEF can be identified in the general population (the Oregon Sudden Unexpected Death Study, Oregon SUDS), and validated in a prospective cohort (the Framingham Heart Study, FHS); and that these predictors will contribute to the mechanistic understanding of SCD, as well as risk stratification methodology. Our specific aims are 1) to identify novel markers of SCD risk in individuals with preserved EF using echocardiographic imaging studies and detailed evaluation of coronary/myocardial abnormalities for improved risk prediction; 2) to investigate the role of right ventricular dysfunction and associated non-cardiac clinical conditions in predicting SCD risk with preserved EF; and 3) to combine genotypes and risk phenotypes, combined with clinical history, EKG parameters, and medication use to improve SCD risk prediction with preserved EF. The critical need to identify risk predictors for SCD with preserved LV systolic function is currently the largest knowledge gap in SCD risk stratification. Over 13 years ago, we initiated the Oregon SUDS to identify novel risk predictors for SCD. Our published analyses have identified several clinical predictors such as echocardiographic LV hypertrophy and specific EKG measures (QTc, QRS and Tpeak-Tend interval) as markers of SCD risk, independent of the LVEF. Furthermore, from our population-based analyses we have reported that the majority of patients (at least 65%) who suffer SCD do not have a severely reduced LVEF. Both the Oregon SUDS and FHS have the track record and resources to deliver essential information required to identify the SCD high-risk subgroups for future investigations. Given the time and expense limitations of traditional clinical trials, it is likely that future SCD trials will also be conducted using randomization within free living cohorts or registries. This proposal presents an opportunity to improve mechanistic understanding of SCD in this group, and potentially improve methodology for SCD risk stratification in individuals with preserved LV systolic function. This novel approach is likely to have a meaningful and significant impact for enhanced prediction and prevention of SCD, a public health problem of substantial magnitude.